Prostate cancer is the most commonly occurring cancer in U.S. men, yet few factors are known to predict which individuals are at increased prostate cancer risk. Prostate cancers often aggregate in families, but do not generally segregate in a Mendelian manner. One explanation for this aggregation without segregation is that predisposition to develop prostate cancer is the result of somatic genetic effects of multiple genes and/or environments acting on an inherited genotype. An understanding of the complex interplay of genetic variability at multiple loci and of environmental agents will facilitate the use of genetic markers to identify individuals at increased risk of prostate cancer. This information could then be used to more effectively apply prostate cancer prevention and control strategies. The objective of the present study is to examine the role of genes that regulate the metabolism of environmental carcinogens in prostate cancer etiology. These genes include cytochromes P450 (e.g. CYP1A1, CYP2D6, and CYP2E1) and the mu or theta classes of the glutathione-S-transferases. Three specific aims are proposed to accomplish this objective. In Specific Aim l, the relationship of each of the candidate genes and the occurrence or age of onset of prostate cancer will be examined. However, it is unlikely that any single gene will be sufficient to account for the complex etiology of prostate cancer. Therefore, the relationship between multiple candidate genes and the occurrence or age of onset of prostate cancer will be examined in Specific Aim 2. It is also likely that endogenous environments and/or exogenous exposures play a significant role in modifying the effects of these genes in prostate cancer risk. Therefore, the interactions of multiple candidate genes, environments, and exposures will be examined in Specific Aim 3. A number of inferences can be made from the information obtained through this study. First, important information about the distribution of alleles at specific candidate genes will be provided. Second, comparisons can be made of the distribution of these alleles among individuals with and without prostate cancer. Differences in these allelic distributions among cancer cases and controls can identify specific single locus or multilocus genotypes that may be biomarkers of prostate cancer risk. Third, interactions of genotypes at multiple loci and environments can provide information about the modification of the effects of these genotypes by specific endogenous environments or exogenous exposures. Finally, before these genes can be used as biomarkers of prostate cancer risk, it will be important to know whether they represent an improvement over other risk factors such as age or family history. The proposed research will study whether prediction of prostate cancer risk is improved by knowledge of candidate genotypes, even after other "traditional" risk factors are known.